PubAg

Main content area

Design and Proof of Programmed 5-Aminolevulinic Acid Prodrug Nanocarriers for Targeted Photodynamic Cancer Therapy

Author:
Wu, Jina, Han, Haijie, Jin, Qiao, Li, Zuhong, Li, Huan, Ji, Jian
Source:
ACS Applied Materials & Interfaces 2017 v.9 no.17 pp. 14596-14605
ISSN:
1944-8252
Subject:
aminolevulinic acid, cytotoxicity, gelatinase A, hydrophilicity, nanocarriers, nanogold, neoplasm cells, neoplasms, pH, peptides, photosensitizing agents, protoporphyrin, zwitterions
Abstract:
5-Aminolevulinic acid (ALA), the precursor of photosensitizer protoporphyrin IX (PpIX), is a U.S. FDA-approved photodynamic therapeutic agent. However, realizing efficient delivery of ALA is still a big challenge as it is hydrophilic and cannot be recognized and selectively accumulated in tumor cells. In this study, matrix metalloproteinase-2 (MMP-2) and pH dual-sensitive ALA prodrug nanocarriers were constructed as a programmed delivery strategy for the targeted delivery of ALA. The nanocarriers were prepared by the co-modification of gold nanoparticles (AuNPs) with hydrazone-linked ALA and MMP-2-activatable cell-penetrating peptides (CPPs). Cationic CPP RRRRRRRR (R8) was shielded by zwitterionic stealth peptide EKEKEKEKEKEKEKEKEKEK (EK10) via MMP-2 substrate peptide PLGLAG. The zwitterionic stealth peptide EK10 is designed to endow ALA prodrug nanocarriers with strong antifouling ability and prolonged circulation time. Upon arriving at the tumor tissue, the shielded cationic CPP R8 can be activated by tumor-microenvironment-overexpressed MMP-2, which enabled enhanced cellular uptake of ALA. The results of drug loading and release, cellular uptake, PpIX generation and accumulation, photodynamic cytotoxicity, and photodynamic tumor inhibition demonstrated that such tumor-microenvironment-sensitive ALA prodrug nanocarriers could be considered as potential candidates for targeted photodynamic cancer therapy.
Agid:
5682510